Method for delivering radiation to an intraluminal site in the body

ABSTRACT

Disclosed is a thin film radiation source, which may be used to deliver a radioactive dose to a site in a body lumen. The source comprises a thin flexible substrate, and a layer of radioisotope attached thereto. The source may further comprise additional layers such as one or more tie layers disposed between the substrate and the radioisotope layer and one or more outer coating layers. In one embodiment, the source is wrapped around an inflatable balloon. Inflation of the balloon at a treatment site positions the source directly adjacent to the vessel wall, and allows irradiation of the site following or simultaneously with a balloon angioplasty, stent implantation, or stent sizing procedure.

RELATED APPLICATION DATA

[0001] This application is a continuation-in-part of Ser. No.09/025,921, filed Feb. 19, 1998.

FIELD OF THE INVENTION

[0002] This invention relates to radiation sources which may betransported on catheters and used to deliver radiation to prevent orslow restenosis of an artery traumatized such as by percutaneoustransluminal angioplasty (PTA).

BACKGROUND OF THE INVENTION

[0003] PTA treatment of the coronary arteries, percutaneous transluminalcoronary angioplasty (PTCA), also known as balloon angioplasty, is thepredominant treatment for coronary vessel stenosis. Approximately300,000 procedures were performed in the United States in 1990 andnearly one million procedures worldwide in 1997. The U.S. marketconstitutes roughly half of the total market for this procedure. Theincreasing popularity of the PTCA procedure is attributable to itsrelatively high success rate, and its minimal invasiveness compared withcoronary by-pass surgery. Patients treated by PTCA, however, suffer froma high incidence of restenosis, with about 35% or more of all patientsrequiring repeat PTCA procedures or by-pass surgery, with attendant highcost and added patient risk.

[0004] More recent attempts to prevent restenosis by use of drugs,mechanical devices, and other experimental procedures have had limitedlong term success. Stents, for example, dramatically reduce acutereclosure, and slow the clinical effects of smooth muscle cellproliferation by enlarging the minimum luminal diameter, but otherwisedo nothing to prevent the proliferative response to the angioplastyinduced injury.

[0005] Restenosis is now believed to occur at least in part as a resultof injury to the arterial wall during the lumen opening angioplastyprocedure. In some patients, the injury initiates a repair response thatis characterized by hyperplastic growth of the vascular smooth musclecells in the region traumatized by the angioplasty. Intimal hyperplasiaor smooth muscle cell proliferation narrows the lumen that was opened bythe angioplasty, regardless of the presence of a stent, therebynecessitating a repeat PTCA or other procedure to alleviate therestenosis.

[0006] Preliminary studies indicate that intravascular radiotherapy(IVRT) has promise in the prevention or long-term control of restenosisfollowing angioplasty. IVRT may also be used to prevent or delaystenosis following cardiovascular graft procedures or other trauma tothe vessel wall. Proper control of the radiation dosage, however,appears to be important to inhibit or arrest hyperplasia without causingexcessive damage to healthy tissue. Overdosing of a section of bloodvessel can cause arterial necrosis, inflammation, hemorrhaging, andother risks discussed below. Underdosing will result in inadequateinhibition of smooth muscle cell hyperplasia, or even exacerbation ofhyperplasia and resulting restenosis.

[0007] The prior art contains many examples of catheter based radiationdelivery systems. The simplest systems disclose seed train type sourcesinside closed end tubes. An example of this type of system can be foundin U.S. Pat. No. 5,199,939 to Dake. In order to separate the radiationsource from the catheter and allow re-use of the source, a deliverysystem is disclosed by U.S. Pat. No. 5,683,345 to Waksman et al. whereradioactive source seeds are hydraulically driven into the lumen of aclosed end catheter where they remain for the duration of the treatment,after which they are pumped back into the container. Later disclosuresintegrated the source wire into catheters more like the type common ininterventional cardiology. In this type of device, a closed end lumen,through which is deployed a radioactive source wire, is added to aconventional catheter construction. A balloon is incorporated to helpcenter the source wire in the lumen. It is supposed that the radioactivesource wire would be delivered through the catheter with a commercialtype afterloader system produced by a manufacturer such as Nucletron,BV. These types of systems are disclosed in Liprie U.S. Pat. No.5,618,266, Weinberger U.S. Pat. No. 5,503,613, and Bradshaw U.S. Pat.No. 5,662,580.

[0008] In the systems disclosed by Dake and Waksman, the source residesin or very near the center of the catheter during treatment. However, itdoes not necessarily reside in the center of the artery. The systemsdisclosed by Weinberger and Bradshaw further include a centeringmechanism, such as an inflatable balloon, to overcome this shortcoming.In either case, the source energies must be high enough to traverse thelumen of the blood vessel to get to the target tissue site in the vesselwall, thus requiring the use of higher energy sources. Higher energysources, however, can have undesirable features. First, the likelihoodof radiation inadvertently affecting untargeted tissue is higher becausethe absorption factor per unit tissue length is actually lower forhigher energy radiation. Second, the higher energy sources are morehazardous to the medical staff and thus require additional shieldingduring storage and additional precaution during use. Third, the sourcemay or may not be exactly in the center of the lumen, so the dosecalculations are subject to larger error factors due to non-uniformityin the radial distance from the source surface to the target tissue. Theimpact of these factors is a common topic of discussion at recentmedical conferences addressing Intravascular Radiation Therapy, such asthe Trans Catheter Therapeutics conference, the Scripps Symposium onRadiotherapy, the Advances in Cardiovascular Radiation Therapy meeting,the American College of Cardiology meeting, and the American HeartAssociation Meeting.

[0009] The impact on treatment strategy is discussed in detail in apaper discussing a removable seed system similar to the ones disclosedabove (Tierstein et al., Catheter based Radiotherapy to InhibitRestenosis after Coronary Stenting, NEJM 1997; 336(24):1697-1703).Tierstein reports that Scripps Clinic physicians inspect each vesselusing ultrasonography to assess the maximum and minimum distances fromthe source center to the target tissue. To prevent a dose hazard, theywill not treat vessels where more than about a 4× differential dosefactor (8-30 Gy) exists between the near vessel target and the farvessel target. Differential dose factors such as these are inevitablefor a catheter in a curvilinear vessel such as an artery, and willinvariably limit the use of radiation and add complexity to theprocedure. Moreover, the paper describes the need to keep the source ina lead transport device called a “pig”, as well as the fact that themedical staff leaves the catheterization laboratory during thetreatment. Thus added complexity, time and risk is added to theprocedure caused by variability of the position of the source within thedelivery system and by the energy of the source itself.

[0010] In response to these dosimetry problems, several more inventionshave been disclosed in an attempt to overcome the limitations of thehigh energy seed based systems. These systems share a common feature inthat they attempt to bring the source closer to the target tissue. Forexample, U.S. Pat. No. 5,302,168 to Hess teaches the use of aradioactive source contained in a flexible carrier with remotelymanipulated windows; Fearnot discloses a wire basket construction inU.S. Pat. No. 5,484,384 that can be introduced in a low profile stateand then deployed once in place; Hess also purports to disclose aballoon with radioactive sources attached on the surface in U.S. Pat.No. 5,302,168; Hehrlein discloses a balloon catheter coated with anactive isotope in WO 9622121; and Bradshaw discloses a balloon catheteradapted for use with a liquid isotope in U.S. Pat. No. 5,662,580. Thepurpose of all of these inventions is to place the source closer to thetarget tissue, thus improving the treatment characteristics.

[0011] In a non-catheter based approach, U.S. Pat. No. 5,059,166 toFischell discloses an IVRT method that relies on a radioactive stentthat is permanently implanted in the blood vessel after completion ofthe lumen opening procedure. Close control of the radiation dosedelivered to the patient by means of a permanently implanted stent isdifficult to maintain because the dose is entirely determined by theactivity of the stent at the particular time it is implanted. Inaddition, current stents are generally not removable without invasiveprocedures. The dose delivered to the blood vessel is also non-uniformbecause the tissue that is in contact with the individual strands of thestent receive a higher dosage than the tissue between the individualstrands. This non-uniform dose distribution may be especiallydisadvantageous if the stent incorporates a low penetration source suchas a beta emitter.

[0012] Additional problems arise when conventional methods, such as ionimplantation, are used to make a radioactive source for IVRT. Hehrleindescribes the use of direct ion implantation of active P-32 in his paper“Pure β-Particle-Emitting Stents Inhibit Neointima Formation in Rabbits”cited previously. While successfully providing a single mode ofradiation using this method, the ion implantation process presents otherlimitations. For example, ion implantation is only about 10 to 30%efficient. In other words, only about one to three of every ten ions putinto the accelerator is implanted on the target, and the remainderremains in the machine. Thus, the radiation level of the machineincreases steadily with consistent use. With consistent use, the machinecan become so radioactive that it must be shut down while the isotopedecays away. Therefore, the isotope used must be of a relatively shorthalf-life and/or the amount of radiation utilized in the process must bevery small, in order to shorten the “cooling off” period. Moreover, themajor portion of the isotope is lost to the process, implying increasedcost to the final product.

[0013] Despite the foregoing, among many other advances in IVRT, thereremains a need for an IVRT method and apparatus that delivers an easilycontrollable uniform dosage of radiation without the need for specialdevices or methods to center a radiation source in the lumen.Furthermore, a need remains for a method to make a source for IVRT whichcan be made without the complications and radioactive waste as seen withion implantation methods.

SUMMARY OF THE INVENTION

[0014] There is provided in accordance with one aspect of the presentinvention, a radiation delivery source. The source comprises a substratelayer having at least a first side and an isotope layer on at least thefirst side of the substrate, wherein the isotope layer comprises a saltor oxide and at least one isotope. In one embodiment, the radiationdelivery source further comprises an outer coating layer. The coatinglayer may comprise any of a variety of materials such as cyanoacrylates,acrylics, acrylates, ethylene methyl acrylate/acrylic acid, urethanes,polyvinylidene chloride, polybutylvinyl chloride, other polymers orcombinations thereof. The outer coating layer may also comprisebiocompatible materials such as heparin.

[0015] Preferably, the isotope in the isotope layer is selected from thegroup of gamma emitters with energies less than about 300 keV includingI-125, Pd-103, As-73, and Gd-153, or the high energy beta group(E_(max)>1.5 meV) including P-32, Y-90 and W/Re-188. Other isotopes notcurrently mentioned, can be utilized by the invention described herein.The selection of these isotopes, however, allows the source to beshielded in a material such as leaded acrylic in commercially availablethickness of 15-30 mm, or in a lead tube of approximately 0.3-0.5 mmwall thickness. Some of the other isotopes which may be deemed suitablefor use in the present invention or for a particular intended use,include Au-198, Ir-192, Co-60, Co-58, Ru-106, Rh-106, Cu-64, Ga-67,Fe-59, and Sr-90. The selection of an isotope may be influenced by itschemical and radiation properties.

[0016] In another aspect of the present invention, a radiation deliverysource is provided having a substrate layer, a tie layer bound thereto,and an isotope layer bound to the tie layer. The tie layer comprises oneor more materials selected from the group consisting of metals, metalsalts, metal oxides, salts, alloys, polyester, polyimide, and otherpolymeric materials. The isotope layer comprises a relatively insolublemetal salt or oxide, and at least one isotope. In one embodiment, thesource further comprises an outer coating layer.

[0017] In one embodiment, the substrate layer is a thin film layer,which may be attached to or which comprises at least a portion of aninflatable balloon.

[0018] In accordance with another aspect of the present invention, thereis provided a method for making a radiation delivery source. The methodcomprises the steps of providing a substrate and coating the substratewith an isotope layer comprising a relatively insoluble salt of at leastone isotope. In one embodiment, the coating step comprises the steps ofcoating the substrate with at least one layer of metal, reacting thelayer of metal to form a metal oxide or metal salt, and exposing (e.g.,dipping) the layer of metal oxide or metal salt to a solution comprisinga plurality of isotope ions to form the isotope layer. In anotherembodiment, the coating step comprises the steps of coating thesubstrate with a layer of metal salt or metal oxide, exposing the layerof metal salt or metal oxide to a fluid comprising a plurality ofisotope ions to form the isotope layer. In one embodiment, the methodfurther comprises the step of coating the isotope layer with a coatinglayer.

[0019] In accordance with a further aspect of the present invention,there is provided a radiation delivery balloon catheter. The ballooncatheter comprises an elongate flexible tubular body, having a proximalend and a distal end. An inflatable balloon is provided on the tubularbody near the distal end thereof. The balloon is in fluid communicationwith an inflation lumen extending axially through the tubular body.

[0020] A thin film radiation source is provided on the balloon, saidthin film source comprising a substrate and an isotope layer. In oneembodiment, a tie layer is provided between the substrate and theisotope layer. In another embodiment, a coating layer is provided overthe isotope layer. The substrate may comprise a portion of the wall ofthe balloon, or a separate substrate layer attached to the surface ofthe balloon. This isotope layer may be bound directly to, or impregnatedwithin, the wall of the balloon. In one embodiment, a tubular outersleeve is provided for surrounding the thin film radiation source andsecuring the radiation source to the balloon.

[0021] In another embodiment, the radiation delivery balloon catheter isprovided with a proximal guidewire access port on the tubular body,positioned substantially distally of the proximal end of the tubularbody, for providing rapid exchange capabilities. In addition to, orinstead of the rapid exchange feature, the catheter may be provided withat least one proximal perfusion port on a proximal side of the balloonin fluid communication with at least one distal perfusion port on adistal side of the balloon, for permitting perfusion of blood across theballoon while the balloon is inflated at a treatment site.

[0022] In accordance with a further aspect of the present invention,there is provided a method of treating a site within a vessel. Themethod comprises the steps of identifying a site in a vessel to betreated, and providing a radiation delivery catheter having anexpandable balloon with a thin film radiation delivery layer thereon.The radiation delivery layer preferably has a substrate layer and anisotope layer. The balloon is positioned within a treatment site, andinflated to position the radiation delivery layer adjacent the vesselwall. A circumferentially substantially uniform dose of radiation isdelivered from the delivery balloon to the vessel wall. The balloon isthereafter deflated and removed from the treatment site.

[0023] In one embodiment, the method further comprises the steps ofpositioning a stent on the balloon prior to the positioning step, andexpanding the stent at the treatment site to implant the stent.

[0024] In accordance with a further aspect of the present invention, thesite identification step in the foregoing method comprises identifying asite having an implanted stent or graft. The balloon is positionedwithin the previously implanted stent or graft and expanded to deliver aradiation dose within the previously implanted stent or graft. Theballoon may either be inflated to a relatively low inflation pressure,to bring the radiation source into contact with the interior wall of thestent or graft without further stent or graft expansion, or inflated toa relatively higher inflation pressure, to further expand the stent orgraft while delivering a radiation dose.

[0025] In accordance with a further aspect of the present invention,there is provided a method of simultaneously performing balloondilatation of a stenosis in a body lumen, and delivering radiation tothe body lumen. The method comprises the steps of identifying a stenosisin a body lumen, and providing a treatment catheter having an elongateflexible tubular body with an inflation balloon near a distal endthereof, and a cylindrical thin film radiation delivery layer on theballoon. The balloon is percutaneously inserted and transluminallyadvanced through the body lumen, and positioned within the stenosis. Theballoon is thereafter inflated to radially expand the vessel in the areaof the stenosis, and simultaneously deliver radiation from the thin filmto the vessel wall.

[0026] In accordance with another aspect of the present invention, thereis provided a method of simultaneously performing a balloon dilatationof a stenosis in a body lumen, delivering a stent, and deliveringradiation to the body lumen. The method comprises the steps ofidentifying a stenosis in a body lumen, and providing a treatmentcatheter having an elongate flexible tubular body with an inflationballoon near a distal end thereof, and a cylindrical thin film radiationdelivery layer on the balloon. The balloon is percutaneously insertedand transluminally advanced through the body lumen, and positionedwithin the stenosis. The balloon is thereafter inflated to radiallyexpand the vessel in the area of the stenosis, expand and deliver thestent and simultaneously deliver radiation from the thin film to thevessel wall.

[0027] In accordance with a further aspect of the present invention,there is provided a method of producing a radiation delivery catheterhaving a target activity. The method comprises the steps of providing acatheter dimensioned for insertion within a body lumen, and providing athin film radiation source having a known radioactive activity per unitlength. A sufficient length of the radiation source is wrapped aroundthe catheter to produce a net radioactive activity of at least about thetarget activity. Preferably, the catheter is provided with a balloon,and the thin film radiation source is wrapped around the balloon. In oneembodiment, the method further comprises the step of providing aprotective tubular sheath around the radiation source, to secure thesource to the catheter.

[0028] Further features and advantages of the present invention willbecome apparent to those of skill in the art in view of the detaileddescription of preferred embodiments which follow, when consideredtogether with the attached drawings and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0029]FIG. 1 is a schematic perspective view of a thin film radiationsource in accordance with the present invention.

[0030]FIG. 1A is a schematic perspective view of an alternate thin filmsource in accordance with the present invention.

[0031]FIG. 1B is a schematic of a cross-section of one embodiment of theradiation delivery source of the present invention having a substratelayer, an isotope layer and a coating layer.

[0032]FIG. 1C is a schematic of a cross-section of one embodiment of theradiation delivery source of the present invention having a substratelayer, a tie layer, an isotope layer and a coating layer.

[0033]FIG. 2 is a schematic side elevational view of a catheterincorporating the thin film source of the present invention.

[0034]FIG. 3 is a schematic side elevational view of an alternatecatheter incorporating the thin film source of the present invention.

[0035]FIG. 4 is an enlarged side elevational cross-sectional viewthrough a balloon incorporating the thin film source of the presentinvention.

[0036]FIG. 5 is an enlarged elevational cross-sectional view of aballoon incorporating the thin film source in accordance with anotheraspect of the present invention.

[0037] The drawing figures are not necessarily to scale.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0038] This invention provides a novel source design, new in terms ofstructure, materials and production methods. The invention can begenerally described as a thin film radioactive source intended for sitespecific delivery of radiation (“brachytherapy”) to an anatomicalstructure. As presently contemplated, one embodiment of the sourcedesign is intended for incorporation into the balloon segment of avascular dilatation catheter such as that disclosed in U.S. Pat. No.5,782,742, Crocker, et al., the disclosure of which is incorporated inits entirety herein by reference.

[0039] Alternatively, the source could be incorporated into traditional“seeds,” or placed on a wire, or on a trocar, or most any other deliverysystem. The thin film can be rolled up into a cylindrical configurationfor insertion and unrolled in-situ for positioning adjacent the vesselwall either by itself or as a laminate on a flexible metal or polymericsupport sheet, such as disclosed in U.S. patent application Ser. No.08/965,900, entitled Radiation Delivery Catheter, filed Nov. 7, 1997 byvon Hoffmann, the disclosure of which is incorporated in its entiretyherein by reference. However, for the sake of simplicity, the presentinvention will be described herein primarily in the context of a balloonstructure for use in intravascular procedures.

[0040] The term “thin film source” is descriptive of the invention'sstructure. Referring to FIG. 1, the source 10 comprises of a thin sheet,or “substrate” layer 12, a chemical attachment or “tie” layer 14 forbinding the isotope, and an isotope species 16. The substrate 12 canconsist of a very thin (1-20 microns, or from about 0.00004 to about0.0008″ thickness) sheet or tubing. At these thicknesses, a wide varietyof biologically compatible materials are very flexible and conforming.Examples of substrates commercially available at these thicknesses areMylar® (polyester), Kapton® (polyimide), and polyethylene terephthalate(PET) sheet or tubing, or even metal foils.

[0041] FIGS. 1A-1C show additional embodiments of the thin film sourceof the present invention. Referring to FIG. 1A, a schematic of across-section of a two-layer embodiment of thin film source is shown.The first or innermost layer is the substrate 12, and the second orouter layer is the isotope layer 16.

[0042] Referring to FIG. 1B, a schematic of a cross-section of thin filmsource, wherein the source has three layers, is shown. The first orinnermost layer is the substrate 12, the second or middle layer is theisotope layer 16, and the outer layer is the coating 17.

[0043] Referring to FIG. 1C, a schematic of a cross-section of afour-layer embodiment of the thin film source of the present inventionis shown. The four layers are the substrate layer 12, tie layer 14,isotope layer 16, and coating layer 17.

[0044] The thin film sources of the present invention are comprised oftwo or more layers of materials. There may or may not be a clear visualor physical distinction between the various layers in the source 10because each layer need not be a discrete structural element of the thinfilm source 10. As the layers bond together to form the source, they maybecome blended, alloyed, intermingled or the like to form what looks andacts like a single layer having a somewhat heterogeneous composition.For this reason, the various layers as defined and used herein areintended to denote the functional characteristics of the components orhelp denote what process steps are used in their formation, whetherthrough the use of discrete structural layers or layers blended withneighboring layers, the selection of which will be apparent to those ofskill in the art in view of the particular materials and componentsused.

[0045] For example, the term tie layer as used herein is intended todenote a functional characteristic which enables securing of the isotopespecies 16 to the substrate 12, whether through the use of a discretestructural layer (such as an adhesive or functionally analogouscomponent) or a surface modification to the substrate 12 (such aschemical activation), the selection of which will be apparent to thoseof skill in the art in view of a particular substrate 12 material andisotope layer 16 material. For example, FIG. 1A schematically representsa substrate 12 having an isotope zone 16 comprising at least oneisotope.

[0046] The thin film sources of the present invention all comprise asubstrate layer or substrate 12. The thickness and composition of thesubstrate layer 12 can be varied widely, depending upon the catheterdesign or the design of the other medical device to which the isotopespecies 16 is to be bound. For example, materials in the thickness ofconventional PTCA balloons (from about 0.0005 to about 0.005 inches) maybe utilized, such as where the balloon itself is used as the substrate12. A balloon substrate may be either of the compliant or non-compliantvariety, as known in the art. In addition, substantially thickersubstrates can be utilized where structural support is desirable as willbe apparent by those of skill in the art in view of the disclosureherein. The substrate 12 may be polymeric or a metal, depending upon thedesired characteristics of the finished product.

[0047] The shape of the source is generally dictated by the geometry ofthe substrate 12. When present, any of the layers described herein,other than the substrate, are disposed over at least one surface of thesource, and may be disposed over the entire surface of the source. Alllayers present in a given embodiment need not cover the same areas ofthe substrate or the entire surface of the source. In one embodiment,the tie layer and isotope layer cover only a portion of the substrate,and the entire substrate is coated with one or more coating layers.

[0048] The thin film sources also all comprise an isotope layer 16. Theisotope layer comprises at least one radioactive isotope. Such isotopesare preferably either beta- or gamma-emitting. The composition of theisotope layer may be of a wide variety of possibilities. In oneembodiment, the isotope layer comprises a collection of individualisotope ions, atoms, or compounds attached to the layer below,preferably in a relatively even distribution. In another embodiment, theisotope layer comprises a metal salt wherein same or all of one ion ofthe salt has been replaced by isotope ions (simple or complex). Such asalt-containing isotope layer may be bound directly to the substratelayer 12 or to a tie layer 14, if present. The isotope layer preferablyhas an isotope density or nuclide density in the range of 10¹⁰-10²⁵atoms/cm², more preferably about 10¹³-10¹⁵ atoms/cm² more preferablyabout 10¹⁴ atoms/cm² and has a thickness of preferably 100-10,000Angstroms thick, more preferably about 500-1500 Angstroms thick.

[0049] As used herein, the term “metal salt” refers to a compoundcomprised of at least one anion and at least one cation. The anions andcations of the metal salt may be either simple (monatomic) ions such asAl³⁺, Cl⁻, Ca²⁺, and Ag⁺, or complex (polyatomic) ions such as PO₄ ³⁻and WO₄ ²⁻. At least one of the ions in the metal salt should comprise ametal. The term “metal” as used herein means all metals, including, forexample, semimetals, alkali metals, and alkaline earth metals.Preferably metals are selected from the transition metals or main groupof the Periodic Table of the Elements. The term “metal salt” as usedherein in its broadest sense can encompass metal oxides.

[0050] The thin film sources of the present invention may furthercomprise at least one tie layer 14. The tie layer 14 lies between thesubstrate 12 and isotope layer 16 and may act to increase the tenacityof attachment of the isotope layer 16 to the substrate 12. The tie layer14 may be any composition or structure which functions to bind theisotope 16 to the substrate 12. The tie layer 14 may comprise adhesives,chemically activated surfaces, mechanical locking structures, a chemicalcoating layer, or a layer of one or more an organic or inorganiccompound. Preferred tie layer materials include metals, alloys, metalsalts, alumina and other metal oxides, polyester, polyimide and otherpolymers. Its chemical composition and structure can be varied,depending on the isotope to be attached. It can be an organic orinorganic material or compound; it must only have the appropriatechemistry to attract and bind the isotope or isotope layer materials.The tie layer may be applied to one or both surfaces of the substrate,depending on factors such as the desired activity, composition orgeometry of the finished product. In one embodiment, the tie layer 14 isa layer of metal or metal oxide, and it is 100 to 10,000 Angstromsthick, more preferably 200 to 500 Angstroms thick.

[0051] The thin film sources of the present invention may furthercomprise one or more coating layers 17. A coating layer 17, can act as asealing means to protect the isotope layer from mechanical abrasion orother injury which could remove radioisotopes from the isotope layer andthus reduce its activity. Although the isotopes in the sources of thepresent invention may be sufficiently adherent without the addition of acoating layer, addition of a coating layer may aid in providingsufficient protection for the device to be classified as a sealedradiation source, i.e. one that has less than 5 nCi of removableactivity. The coating layer may also provide the additional advantage ofsealing or binding the layers of the source together.

[0052] The coating may be a metal or plastic. Plastic coating materialsare preferably biocompatible, but not excessively biodegradable.Preferred materials include cyanoacrylates, acrylics, ethylene methylacrylate, ethylene methyl acrylate/acrylic acid (EMA/AA), urethanes,thermal plastic urethane (TPU) polybutyl vinyl chloride (PBDC),polyvinylidene chloride (PVDC, such as Saran®) polyethylene,polyethylene terephthalate, nylon and the like. Likewise, metal coatingscan be used as well. If the coating is metal, the metal used ispreferably one which is bio-stable. For example, platinum, gold, ortitanium may be vapor deposited on the surface to encapsulate theisotope layer.

[0053] The foregoing thin film structures offer several advantages overexisting source designs. First, the source can conform to almost anyshape, unlike conventional seed or solid wire type sources or even athin metal film. Thus, this type of source is ideal for incorporationinto flexible catheter-like delivery systems.

[0054] Secondarily the sheet can be wrapped several times around itselfwithout substantially stiffening the source 10. For example, thethickness of a typical polyethylene balloon used in angioplasty is atleast about 0.0015″. For an eight micron Mylar sheet, this correspondsto 5 wraps to achieve equivalent thickness. The importance of thisfeature is that the activity of the source can be readily manipulated bythe number of layers of the thin film 10 used to form the final source.Because the activity of the source is proportional to the number ofisotope atoms on the substrate, larger surface areas will have higheratom counts than smaller ones. Thus, the total source activity will beproportional to the surface area of the substrate.

[0055] The ability to increase the activity of the source by wrapping itwithout a material increase in the size of the device is also importantbecause it broadens the number of isotopes that can be used for thisapplication. This is because radioisotopes are different in theirspecific activity, which is the amount of radioactivity per unit isotopemass (Curies/gram). Thus the thin film source 10 of the presentinvention can enable the use of an isotope with low specific activitybut otherwise desirable properties. An example of this is the use oftungsten/rhenium-188 (W/Re-188). This species generates a beta particlewith similar properties to Sr/Y-90, but without the disposal problemsand health risks associated with the long half life (28.5 years) andbone destruction associated with Sr/Y-90. The issue limiting W/Re-188 isthat it has a lower specific activity than Sr/Y-90, and so is moredifficult to achieve adequate activity levels in a small volume. Thismay be overcome using a sufficient surface area of the thin film source10 of the present invention configured as a series of concentricwrappings such as around a balloon.

[0056] The activity of delivery devices which include the thin filmsource 10 of the present invention can be thus increased in a variety ofways depending upon the nature of the delivery device to which thesource is affixed. For example, in the context of a thin film wrappedaround or incorporated into the surface of a continuous circumferentialsupport such as a balloon, the thin film may be wrapped around theballoon anywhere from about one full revolution through about 10 or 20or more revolutions depending upon the desired activity level, andrequired flexibility and collapsed profile characteristics of theballoon.

[0057] In general, for a gamma radiation source the activity of adjacentlayers will be additive, whereas the net activity for a wrapped betasource may be something less than a straight multiple of the number oflayers of radioactive thin film. In many applications, from about 2 toabout 20 layers will be utilized, and, generally, no more than about 6or 8 layers will be utilized for manufacturing reasons and in order tomaintain high catheter flexibility. Optimization of the number of layersof thin film in the context of a particular delivery structure, isotopeand required characteristics can be determined through routineexperimentation by one of skill in the art in view of the disclosureherein. For example, isotope uptake into the substrate can be varied toyield a desired total activity/area, monitored by standard dosimetrymeasurements, using radiochromic film or water phantoms, as described inNational Institute of Standards & Technology publication (NIST, Soares,et al., Washington, D.C. 1997).

[0058] Alternatively, the thin film can be layered in the form of amultilayer stack, when used on a delivery structure which does not havea continuous circumferential surface. Thin film stacks may be useful,for example, in connection with seeds, wires, or a thin metal or plasticsupport of the type disclosed in Ser. No. 08/965,900 to von Hoffmann.

[0059] A further advantage of the thin film configuration of the presentinvention is that the substrate surface area can be increased bydrilling or etching micro holes in the film. As long as the diameter “d”of the holes meets the condition d<2t, where “t” is the thickness of thesubstrate 12, the surface area will increase by the factor (2t/d−1) perhole. Microporous materials are available commercially with wholediameters in the range of from about 0.2 microns to about 5 microns ormore. Thus, this technique is yet another way in which achievableactivities of the source can be increased by increasing availablesurface area of the substrate, while at the same time maintainingflexibility and small size.

[0060] Activity and lifetime of sources can, in part, be manipulated bythe choice of isotope. The relatively rapid time of decay andconcomitant loss of “strength” of short half-life isotopes may presentproduct problems, such as lack of consistent dosing, in addition tomanufacturing problems. Take for example, P-32 implanted on threesources at the same time to a level of 10 μCi using the method describedin the above-cited paper by Hehrlein (Circulation, 1996). Assume allsources are prepared and available for use on day 0. If the first isused immediately, the second after 7.1 days (one half of a half-life),and the third after 14.3 days (one half-life), then the available dose,as compared to the first source, is much less for the second and thirdsources. To achieve a particular dose, a weaker source must be left atthe treatment site for a longer time than a stronger source. Thus, therequired indwell time for a set of catheter-based sources would vary,such that one used 14 days later would need to be left at the treatmentsite twice as long as a source used on day 0.

[0061] Some of the difficulties associated with a lack of consistentdosing which can result with short half-life isotopes, as discussedabove, could be overcome through the use of longer half-life isotopes.If, instead, sources were implanted with an isotope having a 60-dayhalf-life, the dose variation between maximum and minimum over thefourteen-day time frame would be reduced to 15%, and over a 7-day periodto just 8%. The total dose supplied to the tissue by the longerhalf-life isotope will be greater. Effective dose and dose rate,however, remain to be determined. It is generally known that radiationdose can be increased if it is fractionated or given over extendedperiods. Only experimentation can answer the questions of dose and doserate. However, if a long half-life isotope eventually proves effective,the lowest amount of radiation required to perform treatment is alwayspreferable to any higher amount for safety reasons.

[0062] The radioisotopes used in the thin film sources of the presentinvention may be beta or gamma emitters, or both, and may have any of awide range of half-lives, both long and short. The particular isotope,or combination of isotopes as well as the concentration of isotopes inthe source (which determines the dose), can be chosen by one skilled inthe art to serve the needs of a particular application. In a recentpaper presented by Howard Amols at the January 1998 Scripps ClinicConference on Intravascular Radiation Therapy entitled “Choosing theRight Isotope: What's New? Insights into Isotopes or Why Is it so Hardto Find the Ideal Isotope?,” the author states that the best isotopechoice from the perspective of both physics and dosimetry would be aphoton source with an energy greater than 3 MeV and a half-life greaterthan 7 days. Shirish K. Jani, in a lecture entitled “Does the PerfectIsotope Exist?” at the same conference states that the perfect isotopefor vascular brachytherapy would exhibit a low dose gradient, low doselevels to surrounding body tissues, manageable radiation exposure levelsaround the patient and a long half-life. Iodine-125 (I-125, half-life 60days) and tungsten-188/rhenium-188 (W/Re-188, half-life 70 days) arecandidates to meet these criteria, and also have long half-lives. Thus,these are two preferred radioisotopes for use in the present invention.

[0063] Preferred radioisotopes are selected from the group of gammaemitters (or x-ray emitters) with energies less than about 300 KeV suchas I-125, Pd-103, As-73, Gd-153, or the high-energy beta emitters(E_(max)>1.5 meV) including P-32 and W/Re-188, or others as may bedeemed suitable for a particular use. The selection of the isotope maybe influenced by its chemical and radiation properties, and otherisotopes not mentioned herein, but which have properties suitable for aparticular application, can be utilized in the present invention.Preferred radioisotopes used in the thin film sources of the presentinvention may be purchased from Oak Ridge National Laboratory (OakRidge, Tenn.), New England Nuclear (NEN) or any other commercialsuppliers of radioisotopes.

[0064] For all of the attachment systems of the present invention, thenumber of atoms of a particular isotope required on the substrate toachieve a desired activity level is readily calculated. The desiredtotal activity is multiplied by Avogadro's number, and then the resultis divided by the product of Specific Activity and the atomic weight ofthe isotope. The number of isotope atoms per unit substrate area orNuclide Density, is then calculated by dividing again by the totalsource surface area. The corresponding activity density is calculated bydividing the total activity by the substrate surface area. By way ofexample, P-32, with an atomic weight of 32 grams/mole, a specificactivity of 2.857×10⁵ Ci/g (Brown & Firestone, Table of RadioactiveIsotopes, Wiley, 1986), Avogadro's number 6.02×10²³ atoms/mole, and athin film substrate layer of measuring 2.1 cm width by 0.94×N cm length,where N is the number of wraps of the source. Dimensions such as thiswould be appropriate for covering a 3 mm diameter×3 cm length balloon asdescribed elsewhere herein with N wraps. In this case, the substratesurface area is approximately 2 cm² per side, or 4 cm² total per wrap.Estimating the desired activity of the source at 200 mCi, the number ofisotope ions and resulting nuclide and activity densities can becalculated as follows: Ion And Activity Density Calculations P-32, 200mCi Total Activity, Two Coated Sides Number Total Nuclide DensityActivity Density of Wraps Area cm² Atoms/cm² Ci/cm² 1  4 6.59 × 10¹⁵0.50 2  8 1.65 × 10¹⁵ 0.25 3 12  1.1 × 10¹⁵ .016 5 20 6.59 × 10¹⁴ .010 832 4.12 × 10¹⁴ .0063

[0065] As shown by the table, the ability to multiply the number oflayers opens many options to the design of the source. If a high numberof atoms can be attached with a given process, then the number of wrapscan be lower. If a process yields a lower activity density but is verycost effective, more wraps can be used to compensate for the loweractivity density. This feature is important to the designer because therange of achievable activity for the source determines treatment time,product shelf life, and the range of isotope options practical for theapplication.

[0066] The ion implantation process of P-32 can serve as an example ofthese principles in a practical setting. Commercial ion implantationmachines can readily achieve 10¹⁷ ions/cm² on a thin sheet substrate,such as polyimide described in this document. This density level wouldappear to provide more than enough activity on a single wrap for a pureisotope. However, pure isotopes are not readily available and areextremely expensive to manufacture. Those skilled in the art of nuclearphysics will know that P-32, by way of example, can be made from P-31 ina nuclear reactor by neutron bombardment in a process known as an (n,γ)reaction, or it can be made from Sulfur-32 (S-32) in an accelerator in aprocess known as a (n,p) reaction. The processes differ widely in costand resulting isotope purity. The reactor process is relativelyinexpensive, but may yield only about 0.1-0.01% P-32 to P-31; theaccelerator process is more expensive by a factor of 10-100, but theisotope purity can be very high, on the order of 99%. The thin sheetsubstrate thus allows the designer the flexibility to optimize betweensource purity and cost while achieving similar activity level. This inturn allows flexibility toward the activity of the finished source,which effects treatment time and shelf life. The same applies to theother isotope attachment methods discussed herein, and holds trueregardless of the radiation type (gamma or beta) or energy level.

[0067] In accordance with one isotope attachment technique, a thin filmsubstrate is treated with a tie layer composed of a three-dimensionalmatrix with an ionic compound. The choice of the ionic compound is madeto encourage the ion desired to bond within the tie layer. In oneembodiment, the three-dimensional matrix is polyvinyl pyrrolidone (PVP)with an ionic compound containing a Br anion. The PVP matrix is commonlyused in hydrophilic coatings and as a carrier for I₂ in antimicrobialapplications. The three-dimensional matrix is designed to hold andincrease the concentration of ionic compound on the surface. Directattachment of the ionic compound would result in layers on the molecularscale. To accomplish attachment, the treated substrate is placed in anionic solution of I-125 (Na¹²⁵I, a commercially available form ofI-125). I-125 anions exchange with Br anions from the PVP, thusincorporating I-125 into the tie layer and producing a gamma radiationsource. This system can work alternatively in a solution comprising³²P-containing ions such as H₃ ³²PO₄ (a commercially available form ofP-32) to form a beta emitting source.

[0068] In one specific embodiment of the present invention, a generallyrectangular polyester sheet having a width of about 2 cm, a length ofabout 3 cm and a thickness of about 12 microns was coated with a PVP ionexchange surface and soaked in a 0.125 wt % I-125 in NaI solution. Theresulting source was thereafter wrapped around a balloon having aninflated diameter of about 3.0 mm and an axial length of about 30 mm.The sheet length of 3 cm allowed the source to be wrapped around theinflated balloon approximately 3 full revolutions. Thus, in thiscontext, sheet length corresponds to the circumferential direction aswrapped around the balloon, and sheet width corresponds to the axiallength of the source along the balloon. In this embodiment, the activityof the source was approximately 110 milliCuries per centimeter length ofthe substrate sheet. Thus, by providing three full revolutions, a netactivity of about 330 milliCuries was produced, an activity similar tothat disclosed by Teirstein for the Ir-192 (gamma) source used in theScripps study. Using the present invention, the net activity couldconveniently be doubled, for example, by lengthening the substrate sheetto about 6 cm, thereby enabling six revolutions of the substrate aroundthe balloon. This may accomplish a respective reduction in treatmenttime of 50%.

[0069] In cases where adequate activity can be achieved with a singlewrap of the source, a thin tube could be used alternatively to thesheet. For example, PET tubing can be commercially obtained with wallthicknesses similar to the sheet material described earlier(0.0003-0.001 inch). The tube construction may allow for simplerassembly, but otherwise it possesses the same properties as the rolledsheet.

[0070] There are alternative ways of taking advantage of the thin filmstructural properties, however, without utilizing a chemical attachmentsystem for the isotopes. For example, the radioactive isotope or a saltthereof can be attached directly to the sheet without a distinct tielayer 14 through ion implantation, vapor deposition, or sputtering.Thus, for some techniques, a distinct tie layer 14 is omittedcompletely. See FIGS. 1A and 1B.

[0071] Other methods of direct isotope attachment to the substrate canbe considered for metal isotopes. For example, vapor deposition andsputtering can be used to deposit metal isotopes on the substrate. Thelayers in these processes can be controlled to submicron thicknesses,such that all of the physical/mechanical advantages described in theabove paragraphs for chemical attachment systems are maintained:flexibility, ability to adjust activity based on multiple wraps, abilityto utilize less active isotopes.

[0072] Preferred methods of making the isotope layer of the presentinvention may begin with either a substrate to be coated or a tie layerto serve as the place of attachment. Preferred methods comprise exposingsurfaces to fluids comprising reactants or isotopes.

[0073] Such fluids may be gaseous (including plasma and vapor) or liquid(such as solutions), with liquid solutions being preferred. As such, themethods below are described in terms of liquid solutions.

[0074] Some preferred methods of making the isotope layer of thin filmsources of the present invention comprise, in part, either one or bothof the following solution processes: (1) oxidation in an acidic solutionto form a metal salt from a metal; and (2) ion exchange wherein ions ator near the surface of the metal salt are exchanged with those presentin a solution. The first process is based on differences inoxidation-reduction potentials, and the second process is based ondifferences in solubility. These processes will be taken in turn.

[0075] In the first process, the equilibrium is driven by principles ofoxidation-reduction (redox). A metal, in the form of a pure metal orpart of an alloy, may be converted to a metal salt when it is placed insolution comprising an oxidizing agent. Many metals, including those inpreferred embodiments discussed below, can be readily oxidized insolution to form metal cations, which may then form salts with anions insolution.

[0076] Whether or not a particular reaction of an oxidizing agent and ametal will occur spontaneously can be predicted by reference to astandard table of half-cell potentials such as that in CRC Handbook ofChemistry and Physics, (CRC Press). If the sum of the potentials of theoxidation half-reaction and the reduction half-reaction is positive,then the reaction will occur spontaneously.

[0077] For example, it can be predicted that when silver is added to anacid solution of sodium chlorite, the silver will be oxidized. Whenadded to the solution, sodium chlorite (NaClO₂) disproportionates toform hypochlorous acid and chlorine dioxide, which is capable ofoxidizing silver as shown below:

Ag→Ag⁺+e⁻(ox) Emf=−0.80 V

ClO₂+e⁻→ClO₂(red) Emf=1.16 V

Ag+ClO₂+e⁻→Ag⁺+ClO₂ Emf=0.36 V

[0078] In addition to the reaction shown above, the hypochlorous acidundergoes a redox reaction whereby chloride ions are produced, whichthen couple with the silver cations to form silver chloride.

[0079] The second process is a solubility-driven ion exchange. When, forexample, two anions are placed in solution with a given cation, there isa driving force which results in the formation of the metal salt whichis less soluble/more insoluble. Because it is difficult to comparesolubilities and thus predict behavior when the relative terms “soluble”and “insoluble” are used, solubility is related to a type of equilibriumconstant, the solubility product (K_(sp)), in order to quantify thedegree of solubility for a given compound. The solubility product isequal to the concentrations of the dissociated ions of the salt atequilibrium, that is for salt AB, K_(sp)=[A⁺][B⁻] wherein [A⁺] and [B⁻]are the concentrations of the A cation and the B anion, respectively. Ifa salt is fairly soluble, the concentrations of its component ions insolution will be relatively high, leading to a relatively large K_(sp).On the other hand, if a salt is fairly insoluble, most of it will be insolid form, leading to low concentrations of the ions and a relativelysmall K_(sp). Thus, when comparing two salts of the same metal, the saltwith the lower K_(sp) is the more insoluble of the two. Solubilityproducts for most common compounds can be found in reference texts suchas the CRC Handbook of Chemistry and Physics(CRC Press).

[0080] The salts silver chloride (AgCl, K_(sp)=1.77×10⁻¹⁰) and silveriodide (AgI, K_(sp)=8.51×10⁻¹⁷) can be used to illustrate the principleof solubility driven ion exchange. The solubility products for thesecompounds are both fairly low, but K_(sp) for silver iodide is lower bynearly 7 powers of ten, indicating that it is more insoluble than silverchloride. Thus, if solid silver chloride is placed in a solutioncontaining iodide ions, the equilibrium lies on the side of the silveriodide, and the chloride ions will exchange with the iodide ions so thatthe more insoluble silver iodide is formed. On the other hand, if silveriodide is placed into a solution containing chloride ions, the ionexchange will not take place. In this manner, chloride ions in silverchloride coated on the surface of a substrate can be replaced by ¹²⁵Ianions to form a radiation source of the present invention.

[0081] The metal salt layer which is the starting point for the abovesolution ion exchange process may be formed by a redox process such asthat described above, or it may be applied directly by means ofsputtering, vapor deposition, or other techniques known in the art.Alternatively, if a redox process described above is performed using anoxidizing solution containing a radioisotope, for example H₃ ³²PO₄, theradioisotope-containing metal salt layer may be obtained directly,eliminating the need for the ion exchange.

[0082] Another preferred method for making thin film sources of thepresent invention comprises oxidizing a metal, such as those bound to orincorporated in the substrate, and then binding an isotope to the metaloxide. The step in which the metal is oxidized preferably occursspontaneously in air. Thus, metals such as aluminum and copper, whichreadily and spontaneously undergo oxidation to form their respectiveoxides, are preferred. Oxide formation occurs when the metal is exposedto air, but may be enhanced or increased by exposure to oxygen-enrichedatmospheres or increased temperature. The binding of the isotope ispreferably performed by immersing the metal oxide in a solutioncontaining isotope ions, either simple or complex. The attractionbetween the metal oxide and the isotope ions is such that the isotopeions will bind to the metal oxide rather than existing free in solution.This binding or “plating” process may occur either with or withoutdisplacement of ions from the metal oxide.

[0083] There are several advantages to using the processes above toplace active isotopes on a source as opposed to the ion implantation ofradioisotopes and nuclear bombardment. One advantage is that unwantedisotopes are not formed. As discussed above with reference to Hehrlein'177, neutron activation of a metal-containing source produces numerousisotopes, making it very difficult to control the dose provided by thesource.

[0084] Another advantage of the present method is that it does notcreate large quantities of radioactive waste. By using the correctquantity of radioisotope solution, very little waste is produced.Isotopes which are not incorporated into a given source remain insolution and may be used to form another source. Unlike radioactive ionimplantation, there is no stray isotope-filled machine chamber that mustbe cleaned and safely discarded or taken out of use and allowed to“cool.”

[0085] Yet another advantage of the present method is that it allows useof isotopes which cannot be readily obtained on a solid source by theother means known in the art. With the proper choice of materials andsolutions and the disclosure herein, one skilled in the art would beable to create a reaction scheme to make a salt containing most any ofthe desirable therapeutic radioisotopes. Furthermore, by usingparticular long-lived isotopes, a radiation source with a longerhalf-life can be produced that is capable of delivering a dose with lessvariation between maximum and minimum. Use of an isotope with a longerhalf-life may provide for a radiation source which is capable oflowering the amount of radioactivity necessary to perform its functionover that which incorporates a short-lived isotope.

[0086] Another advantage of the present invention is that theradioisotopes are held by strong atomic-level bonding interactions, andwhich are highly resistant to leaching or release under physiologicalconditions or during handling. Additionally, the use of ionic bonding isespecially useful for radioisotope species such as iodine-125, as thesalt form holds the normally volatile iodine atoms in place.

[0087] Another benefit to the solution processes of the presentinvention is that the density of activity of a given isotope or multipleisotopes may be controlled by simply controlling the time of immersionand/or the density and amount of metal salt or tie layer on the source.

[0088] Another advantage of the thin film source is that the structurelends itself to batch processing. The coating step can be done inrelatively large volumes using common chemical attachment techniquesfound in the photographic film and semiconductor industries. Radioactiveisotopes are commonly provided in solutions, so the final productionstep of adding the isotope may be as simple as soaking the coatedsubstrate in the isotope solution. This can be simply performed in verysmall or very large sheet sizes. The ability to perform this step insmall batches is advantageous because the amount of radiation in processcan be adjusted to suit the radiation capabilities of the manufacturer.

[0089] The basic method, as discussed in part above, comprises providinga substrate and forming a coating comprising an insoluble metal saltwith at least one radioactive isotope species thereon.

[0090] One preferred embodiment of thin film source of the presentinvention is that which has an isotope layer comprising thegamma-emitting isotope ¹²⁵I. As mentioned previously, ¹²⁵I meets thecriteria of an “ideal” isotope as defined by Amols and Jani. One methodfor making a thin film source having an isotope layer comprising ¹²⁵I isthat which uses both solution methods discussed above. First, asubstrate is provided that comprises silver or elemental silver isattached to the surface of the substrate using well-known methods suchas ion implantation, vapor deposition, sputtering, electroplating, orrolling. The silver is then converted to silver chloride (AgCl) via anoxidation-reduction solution process such as that described above whichuses an acidic solution of sodium chlorite to reduce the silver andproduce silver chloride. Then the silver chloride-coated source isimmersed in an ion exchange solution comprising sodium iodide in theform of Na¹²⁵I, wherein the AgCl is converted to Ag¹²⁵I on the surfaceof the source. This manufacturing process may be performed quickly,easily and efficiently. In addition, the I-125 with a half-life of 60days would provide an equivalent or lower dose of radiotherapy for alonger period of time.

[0091] As an alternative to the above method, silver chloride could bedirectly deposited to the surface of the thin film source by means ofvapor deposition or other method known in the art, and then immersed inthe ion exchange solution containing Na¹²⁵I.

[0092] In one specific embodiment of the present invention, a silverfoil having a surface area of 4cm² was immersed in a solution of 6M HCland 1 M NaClO₂ in a 10:1 ratio. A portion of the silver was therebyconverted to silver chloride. The foil was then immersed in a bathhaving about 2 ml of a solution. The solution in the bath containedabout 0.07% Na¹²⁵I in NaI, and was prepared by dissolving 0.5 mg NaI in2 ml water and adding 4.6 mCi ¹²⁵I into the solution. Followingimmersion, the resulting activity of the foil was measured at 2 mCi,which, when the amount of carrier (non-radioactive) iodine is factoredin, corresponds to about 10¹⁸ atoms of iodine attached to the sheet. Ina carrier free solution, this number of I-125 ions would result in anactivity of 3 Ci per 4 cm² of substrate. This is 30,000 times therequired activity for a 10 μCi source..

[0093] Another preferred embodiment of thin film source of the presentinvention is that which has an isotope layer comprising ³²P. A thin filmsource having an isotope layer comprising ³²P can be made by methodssimilar to that described above for ¹²⁵I using P-32 in the form oforthophosphoric acid (H₃ ³²PO₄) (New England Nuclear). First, asubstrate is provided. The substrate may be manufactured to contain zincor a zinc alloy, or the substrate may be coated with zinc or a zincalloy by vapor deposition or other methods known in the art. The zinc isthen converted to a salt such as zinc fluoride (ZnF₂, K_(sp)=3.04×10⁻²)via an oxidation-reduction process similar to that discussed above. Thesource is then activated by immersing the zinc fluoride-coated source ina solution containing phosphate ion in the form of ³²PO₄ ³⁻ or a solublephosphate salt, whereby the more soluble fluoride ion is exchanged forphosphate to form zinc phosphate (Zn₃(PO₄)₂, K_(sp)=5×10⁻³⁶).

[0094] Alternatively, the substrate may be directly coated with zincfluoride or other similarly insoluble salt by vapor deposition or othermeans known in the art, and then placed in an ion exchange solution.Another alternative is to use a solution containing H₃ ³²PO₄ in theoxidation step so that the zinc is directly converted to zinc phosphatecontaining the radioisotope, thus eliminating the ion-exchange step. Yetanother alternative is to deposit or form calcium fluoride (CaF₂,K_(sp)=1.61×10⁻¹⁰) and then expose this to a source of phosphate(orthophosphate) such as H₃ ³²PO₄ or Na₃ ³²PO₄.

[0095] There is an additional advantage to using zinc phosphate in theisotope layer. Zinc phosphate is a stable molecule and is often used inthe automotive industry for paint adhesion to galvanized steel. Zincphosphate has anticorrosive characteristics of its own, and has beenused in the past to increase the corrosion resistance of steel. A zincphosphate coating on a source made of steel, such as a wire or seed, maybe an advantage to the source even in the case that it is not used as aradiation delivery device.

[0096] Yet another preferred embodiment of thin film source of thepresent invention is that which has an isotope layer comprisingtungsten-188 (W-188 or ¹⁸⁸W). Tungsten-188 undergoes beta decay tobecome rhenium-188 (Re-188 or ¹⁸⁸Re). Rhenium-188 undergoes beta decayas well, but emits a much higher energy particle than in W-188 decay.The W-188 has a much longer half-life than does Re-188, thus the W-188almost continuously creates more Re-188. This process is known as“generator,” and these generator isotopes are referred to together bythe shorthand W/Re-188 to indicate the relationship between the species.Generators are attractive for use in radiation delivery devices becausethey combine the energy levels of a short half-life species with thedurability of the long half-life species. It is a general rule thatparticle energy and half-life are inversely proportional, and that longhalf-life species are more economical and practical to work with thanshort half-life species.

[0097] W/Re-188 is a beta emitting isotope with an energy about 10%higher than P-32. Where I-125 was discussed as a highly favorable gammaemitting isotope, W/Re-188 fits the criteria of both Amols and Jani fora highly favorable beta emitting species for IVRT. The advantage of theW/Re-188 source would be that the source would provide a dose whichcould be consistently administered over a long period of time. Thehalf-life of W-188 is 70 days as compared to 14 days for the P-32. Thisrepresents a consistent dose rate as Re-188, itself a beta emittingisotope, is being produced by the decay of tungsten for a longer periodof time.

[0098] Tungsten, in the form of tungstate ion (WO₄ ²⁻) may be readilyattached to an oxidized aluminum surface to produce aW/Re-188-containing thin film source of the present invention. Analuminum oxide surface may be attached to the source by sputteringAl₂O₃, or Al can be attached by implantation or deposition, followed byan oxidation step. Ambient environment will facilitate the formation ofAl₂O₃ from aluminum which can be accelerated by increasing thetemperature and/or using an oxygen-rich atmosphere. The aluminum oxidesurface may then be immersed in a tungstate containing solution, such asan acidic solution of sodium tungstate (Na₂ ¹⁸⁸WO₄), in order to attachthe W-188 to the alumina surface.

[0099] Tungsten may also be applied together with a phosphate in amanner similar to that disclosed by Larsen in U.S. Pat. No. 5,550,006,which is hereby incorporated into the present disclosure by thisreference thereto. The method disclosed in Larsen is claimed for use inincreasing adhesion of organic resists for printed circuits. The methodwas used to perform a phosphate conversion coating onto copper. Thismethod may find its application in the radiation delivery device of thepresent invention in that many polymers and metals other than copper maybe coated with this solution. In this method, phosphate may be in theform of ³²PO₄ ³⁻, tungstate may be in the form of ¹⁸⁸WO₄ ²⁻, or anycombination of the isotopes in radioactive or stable form may be used.

[0100] Sources employing combinations of various isotopes provideanother preferred embodiment in that beta-emitting isotopes may becombined with gamma-emitting isotopes where gamma isotopes can deliverdosage to greater depths.

[0101] Thin film sources comprising other metals, metal salts, andisotopes can be made by procedures similar or analogous to the preferredembodiments disclosed above, using materials appropriate for thechemistry of the isotope to be included, as can be determined by oneskilled in the art in view of the disclosure herein.

[0102] In some embodiments of the thin film source of the presentinvention, it may be desirable to provide a tie layer, onto which theisotope layer will be placed. The tie layer may comprise adhesives,chemically activated surfaces, a chemical coating layer, or an organicor inorganic compound. Preferred tie layer materials include metals,alloys, metal salts, metal oxides, PVP, and other polymeric materials.

[0103] For some polymeric tie layers, the nature of the tie layer 14will depend on the isotope to be attached. Many different coatings andattachment technologies are available, and new ones can be developed asapplications are developed. For example, Iodine-125 (I-125) can be boundto the substrate by passing it over a substrate coated with a polyvinylpyrolidone (PVP) as discussed previously. Other preferred polymeric-typetie layers comprise polymeric materials such as polyesters andpolyimides.

[0104] Another preferred type of tie layer is the metal-type that whichcomprises a thin layer of metal, metal oxide, metal salt, or alloy.Depending upon the composition of the other layers and materials in thesource, depositing a metal-type tie layer may allow an “alloying”process to take place between the metal of the tie layer and any metalspresent in the isotope layer. This may serve to enhance the tenacity ofattachment of the metal salt, and hence the isotope. This may also occurif the tie layer comprises more than one metal or if more than one tielayer is used in making the source. Alloying of this type is common inthe semiconductor industry, wherein a chromium layer is used as aninitial layer in the deposition of gold. The chromium is alloyed withthe gold in order to increase the strength at which the gold is bound tothe substrate. If, for example, the isotope layer comprises a zinc salt,a metal such as copper or aluminum may be used as the tie layer. The tielayer may also be in the form of an oxide that provides oxygen tochemically bind the atoms of the metal salt layer thereby increasing thetenacity of attachment.

[0105] A metal-type layer to which the isotope layer is attached maycomprise any suitable metal, metal oxide, metal salt or alloy. The layermay be deposited by vapor deposition, sputtering, ion plating, ionimplantation, electrodeposition, or other method. When the tie layer ispresent, there may or may not be a clear distinction between the tielayer and the isotope layer. In performing its function, and dependingon the chemistry of the materials involved, the tie layer may becomeblended, alloyed or intermingled with the isotope layer, thus blurringthe lines between the layers. For many of the same reasons, thedistinction between the tie layer and a metal-containing substrate layermay also be blurred. In these cases, the term tie layer is meant to be afunctional or process-defining definition, rather than a reference to aphysically distinct layer of the thin film source.

[0106] In another type of system that can be constructed, the tie layer14 can incorporate a metal exchange surface, which will attach Pd-103 inthe form of palladium metal drawn directly from solution. For example,the substrate layer, made from polyimide as disclosed previously, can becoated with reactive metals such as copper, aluminum, or chromium usingcommonly available techniques such as vapor deposition or sputtering.The coated substrate is then placed in a solution containing theisotope. The difference in oxidation-reduction (redox) potential betweenthe coating metal and the isotope causes the isotope to deposit on thesurface of the substrate film. This system can also be used to attachW-188 from a solution of tungsten salts or other metal salt isotopes aswell.

[0107] Metal isotope species, such as Palladium-103 (Pd-103) orTungsten/Rhenium-188 (W/Re-188) or Gd-153 can be attached byincorporating a chelating agent onto the polymer substrate, and thensoaking the sheet in a solution of Palladium salts, Tungsten salts orGadolinium salts. These types of chemical technologies can beincorporated into the source design described herein.

[0108] An experiment was done to test the effectiveness of using acopper tie layer to enhance the attachment of zinc fluoride onto aMylar® sheet. A layer of ZnF₂ was placed on a first sheet of Mylar byvapor deposition. On a second sheet of Mylar, a layer of copper wasplaced by vapor deposition, followed by deposition of a layer of ZnF₂.The sheets were each placed into solutions of H₃ ³²PO₄ having similaractivities and allowed to react for several hours. The P-32 activity wascounted via scintillation counting. It was found that the sheet havingthe copper tie layer resulted in a greater adsorption of P-32: 71.6% forCu/ZnF₂ vs. 56% for ZnF₂ after 1 hour; and 98.4% for Cu/ZnF₂ vs. 86% forZnF₂ after 24 hours. Thus, after a significant period of time, thecopper tie layer appears to promote and maintain adherence of the zincsalt to the Mylar surface, and can result in a source which hassignificantly more activity and adhesion than that without the coppertie layer.

[0109] Although the sources of the present invention may have isotopeswhich are sufficiently adherent without further treatment, in someembodiments of the present invention, it may be desirable to place anouter coating on the thin film source. An outer coating can providefurther advantages for the thin film source of the present invention inthat the coating can help provide additional means to bind the layers ofthe source together. Perhaps more importantly, an outer coating canincrease the abrasion resistance of the source.

[0110] Sealed radioactive sources are those which have less than 5 nCiof removable activity. By providing a coating on the source which coversat least the isotope layer, the source can be protected from unwantedloss of activity due to mechanical abrasion of the surface of thesource. This may be important, both for providing safe devices for thepatient which leave radioisotopes behind only where they are desired,and for monitoring dosage to ensure that the dose which is to beprovided by a source will actually reach the treatment site, and not besignificantly diminished due to loss of isotope from abrasion which mayoccur during implantation. It also helps insure that, once the source ispositioned for treatment, the radioisotopes will remain at that site andnot be washed downstream.

[0111] Coating materials are preferably biocompatible, but notexcessively biodegradable. Preferred materials include polymericmaterials including cyanoacrylates (Loctite, Hartford, Conn.), acrylics,ethylene methyl acrylate (Exxon Chemical Co., Houston, Tex.), ethylenemethyl acrylate/acrylic acid (EMA/AA) (Exxon Chemical Co., Houston,Tex.), urethanes and thermal plastic urethane (TPU) (BF Goodrich,Richfield, Ohio), PVDC, PBVC, PE, PET, and combinations thereof. Otherpreferred coatings may comprise other biocompatible materials, drugs orsimilar compounds, such as heparin. Many methods are available toperform the coating process, such as dip or immersion coating, spraycoating, spin coating, gravure or shrink wrap tubing. If curing isrequired, the curing technique may be any of the various techniquesavailable, such as air, heat, or UV. Preferably the thickness of thecoating which is formed is 1 μm to 30 μm more preferably 10 μm to 20 μm.

[0112] One preferred embodiment of the present invention has a coatingthat is formed with cyanoacrylate. Another preferred coating layer isthat formed by ethylene methyl acrylate/acrylic acid (EMA/AA) polymer.An aqueous dispersion of this coating material, preferably having aviscosity less than 100 centipoise, allows for use of any of theabove-mentioned coating methods. UV curable polyurethane acrylate isalso useful as a coating layer material. Yet another preferred coatinglayer is that formed by SARAN. Such a layer may be formed, for example,by immersing the source or a portion thereof into a melt of SARAN or asolution containing SARAN.

[0113] The coating layer may also be formed by a spin coating process.Spin coating the thin film source finds advantage in the flexibility touse coating materials having a wide range of viscosities. Low viscosityliquids may be spun on slowly, while a higher viscosity liquid may bespun at a higher velocity to maintain a thin coating. The substrate maybe held in place by fixturing or by vacuum during the spin coatingprocess. In an experiment, a dispersion of cyanoacrylate in acetone wasdispensed on top of the metal salt surface while the substrate wasrotated at 8000 rpm for five minutes. The resulting thickness of thecoating was about 6.5 μm (0.00025 inch). When this specimen, having thespin-coated surface curable coating of cyanoacrylate was extracted insaline for 8 hours at 50° C., the amount of radioactivity extracted wasnegligible.

[0114] In another experiment, two sources were tested to demonstrate theeffectiveness of the coating layer by measuring the amount of removableisotope on coated and uncoated sources. Both sources comprised a Mylarthin film substrate and a ZnF₂/Zn₃(³²PO₄)₂ isotope layer, with thecoated source further comprising a cyanoacrylate coating layer made bydip coating an uncoated source. The test was performed on each source bywiping it with a cotton swap three times on each side. The activity ofthe swab was measured by scintillation counting. It was found that theamount of removable activity on the uncoated Mylar-based source was6.76%, while on the coated source the removable activity was merely0.050%.

[0115] In making some embodiments of the thin film source of the presentinvention, it may be desired that one or more portions of the source orsubstrate are not covered or coated by particular layers or portions oflayers. In such embodiments, the source may be made by the use ofmasking techniques. In such a technique, the portions of the source orsubstrate which are to be left alone for a particular step or steps arecovered with a piece of a material to serve as the mask. The otherportions not covered by the mask are treated (reacted, coated) and thenthe mask is removed. For example, it may be preferred to have a smallborder of substrate surrounding the portion of the source onto which theisotope layer is placed. Such an arrangement may be preferred to reducecoating of the side surfaces of the substrate by the isotope layer,reduce edge effects or to enable several distinct and separate sourcesto be prepared on a single sheet of substrate having spaces therebetweenwhich are not coated by isotope to that the individual sources may beseparated once they are completely prepared without the risk ofradioactive contamination of the blade or other implement which is usedto cut or separate the individual sources.

[0116] In one embodiment, a plurality of sources comprising a Mylarsubstrate, alumina tie layer and CaF₂/³²PO₄ isotope layer are made usinga mask. In this method, the Mylar sheet is placed between a plate and amask. The plate may be formed of glass, metal or other suitablematerial. The mask is a stainless steel sheet from which severalrectangular-shaped portions have been removed. The three pieces (plate,Mylar, mask) are secured together and then placed in a chamber. Alumina,which forms the tie layer, is then deposited on the rectangular-shapedportions of the Mylar which have been left exposed by the mask. Calciumfluoride is then deposited on the alumina. The mask is then removed, andthe entire sheet placed in an ion-exchange bath containing ³²PO₄ ³⁻ ionsto complete formation of the isotope layer. One or more outer coatinglayers may optionally be placed on the sheet prior to separation of theindividual sources. The sources may also be coated individuallyfollowing separation, such as following incorporation onto a ballooncatheter.

[0117] The masking technique is described above in terms of makingsources having a border of substrate surrounding an active areacomprising a tie layer and isotope layer coating the substrate. Althoughdescribed as such, the masking technique or variations thereof as wouldbe apparent to one skilled in the art, may be used for other purposes inmaking the sources of the present invention, such as placing a coatinglayer on selected portions of the source, and placing different tielayers on different portions of the source.

[0118] Referring to FIG. 2, there is disclosed a radiation deliverycatheter 18 incorporating the thin film source 10 in accordance with oneaspect of the present invention. Although the description below isprimarily directed to the radiation aspect of the invention, cathetersembodying additional features known in the vascular dilatation art, suchas carrying implantable stents, drug delivery, perfusion and dilatationfeatures, or any combination of these features, can be used incombination with the balloon of the present invention as will be readilyapparent to one of skill in the art in view of the disclosure herein.

[0119] The catheter 18 generally comprises an elongate tubular body 19extending between a proximal control end 20 and a distal functional end21. The length of the tubular body 19 depends upon the desiredapplication. For example, lengths in the area of about 130 cm to about150 cm are typical for use in radiation delivery by way of a femoralaccess following or during percutaneous transluminal coronaryangioplasty.

[0120] The tubular body 19 may be produced in accordance with any of avariety of known techniques for manufacturing balloon-tipped catheterbodies, such as by extrusion of appropriate biocompatible plasticmaterials. Alternatively, at least a portion or all of the length oftubular body 19 may comprise a spring coil, solid walled hypodermicneedle tubing, or braided reinforced wall, as is understood in thecatheter and guide wire arts.

[0121] In general, tubular body 19, in accordance with the presentinvention, is provided with a generally circular exteriorcross-sectional configuration having an external diameter with the rangeof from about 0.02 inches to about 0.065 inches. In accordance with onepreferred embodiment of the invention, the tubular body 19 has anexternal diameter of about 0.042 inches (3.2 F) throughout most of itslength for use in coronary applications. Alternatively, generallytriangular or oval cross-sectional configurations can also be used, aswell as other noncircular configurations, depending upon the number oflumen extending through the catheter, the method of manufacture and theintended use.

[0122] In a catheter intended for peripheral vascular applications, thetubular body 19 will typically have an outside diameter within the rangeof from about 0.039 inches to about 0.085 inches. Diameters outside ofthe preferred ranges may also be used, provided that the functionalconsequences of the diameter are acceptable for the intended purpose ofthe catheter. For example, the lower limit of the diameter for tubularbody 19 in a given application will be a function of the number of fluidor other functional lumens, support structures and the like contained inthe catheter, and the desired structural integrity.

[0123] In general, the dimensions of the catheter shaft and balloon canbe optimized by persons of skill in the art in view of the presentdisclosure to suit any of a wide variety of applications. For example,the balloon of the present invention can be used to deliver radiation tolarge and small arteries and veins, as well as other lumens, potentialspaces, hollow organs and surgically created pathways. The presentinventor contemplates radiation delivery to the esophagus, trachea,urethra, ureters, fallopian tubes, intestines, colon, and any otherlocation accessible by catheter which may benefit from radiationdelivery. This includes surgically created lumens such as, for example,transjugular intrahepatic portosystemic shunts and others which will berecognized by those of skill in the art. Thus, although the presentinvention will be described herein primarily in terms of coronary arteryapplications, it is understood that this is for illustrative purposesonly, and the present invention has much broader applicability in thefield of radiation delivery.

[0124] Tubular body 19 must have sufficient structural integrity (e.g.,“pushability”) to permit the catheter to be advanced to a treatment sitesuch as distal arterial locations without buckling or undesirablebending of the tubular body 19. Larger diameters generally havesufficient internal flow properties and structural integrity, but reduceperfusion in the artery in which the catheter is placed. Larger diametercatheter bodies also tend to exhibit reduced flexibility, which can bedisadvantageous in applications requiring placement of the distal end ofthe catheter in a remote vascular location. In addition, lesionsrequiring treatment are sometimes located in particularly small diameterarteries, necessitating the lowest possible profile.

[0125] As illustrated schematically in FIG. 2, the distal end 21 ofcatheter 18 is provided with at least one inflatable balloon 22. Theproximal end 20 of catheter 18 is provided with a manifold 23 which mayhave one or more access ports, as is known in the art. Generally,manifold 23 is provided with a guide wire port 24 in an over the wireembodiment and a balloon inflation port 25. Additional access ports areprovided as needed, depending upon the functional capabilities of thecatheter 18.

[0126] The balloon 22 can also be mounted on a rapid exchange typecatheter, in which the proximal guidewire port 24 would not appear onthe manifold 23 as is understood in the art. In a rapid exchangeembodiment, the proximal guidewire access port 24 is positioned alongthe length of the tubular body 19, such as between about 1 and about 20cm from the distal end of the catheter.

[0127] Referring to the embodiment of the balloon illustrated in FIG. 2,a focal or enlarged zone 32 is positioned between a proximal referencezone 28 and a distal reference zone 30. The relative lengths of each ofthe three zones may vary considerably depending upon the intended use ofthe balloon. In general, suitable dimensions of the balloon, both interms of diameters and lengths, as well as other catheter dimensions,are disclosed in U.S. Pat. No. 5,470,313 to Crocker, et al., entitledVariable Diameter Balloon Dilatation Catheter, the disclosure of whichis incorporated in its entirety herein by reference.

[0128] In one particular application, the central zone 32 has an axiallength of about 25 mm, and each of the proximal zone 28 and distal zone30 have an axial length of about 5 mm. At an inflation pressure of about8 atmospheres, the proximal zone 28 has an outside diameter of about 3mm, and the central zone 32 has an outside diameter of about 3.4 mm. Thesame balloon at 18 atmospheres inflation pressure has an outsidediameter of about 3.1 mm in the proximal zone 28 and an outside diameterof about 3.5 mm in the central zone 32. That particular balloon wasconstructed from PET, having a wall thickness of about 0.0006 to about0.0008 inches.

[0129] In accordance with an alternative embodiment of the balloon ofthe present invention, illustrated in FIG. 3, the balloon 26 has agenerally cylindrical inflated profile throughout its axial workinglength such as with conventional PTCA balloons. Either the steppedballoon of FIG. 2 or the cylindrical balloon of FIG. 3 can be readilyprovided with the radiation source 10 discussed below in accordance withthe present invention.

[0130] The overall dimensions of any particular balloon 22 or 26 will begoverned by the intended use, as will be well understood to those ofordinary skill in the art. For example, balloons can be inflatable to adiameter of anywhere within the range of from about 1.5 mm to about 10mm. For coronary vascular applications, the central zone 32 or overallballoon 26 will normally be inflatable to a diameter within the range offrom about 1.5 mm to about 4 mm, with balloons available at about every0.25 mm increment in between.

[0131] The proximal zone 28 and distal zone 30 are generally inflatableto a diameter within the range of from about 1.25 mm to about 9.5 mm.For coronary vascular applications, the proximal and distal zones 28, 30are preferably inflatable to a diameter within the range of from about1.25 mm to about 3.5 mm.

[0132] The axial length of the central section 32 can be variedconsiderably, depending upon the desired radiation delivery length aswill become apparent. For example, the axial length of the centralsection 32 may be anywhere within the range of from about 0.5 cm toabout 5.0 cm or longer. For coronary vascular applications, the axiallength of the central section 32 will normally be within the range offrom about 0.5 cm to about 2.0 cm, if the balloon is designed to deliverradiation as well as simultaneously perform conventional PTCA. In aradiation delivery balloon which is not intended to perform PTCA, theaxial length of the central zone 32 may exceed the typical length of thelesion, and, in coronary vascular applications, the axial length may bewithin the range of from about 0.5 cm to about 5 cm or longer.

[0133] The axial length of the proximal zone 28 and distal zone 30 mayalso be varied considerably, depending upon the desired performancecharacteristics. In general, axial lengths of the cylindrical portion ofthe proximal zone 28 and distal zone 30 of at least about 3 mm appearuseful.

[0134] Referring to FIG. 4, there is disclosed a radioactive balloon inaccordance with the present invention, configured as in FIG. 3. Theballoon 26 comprises a radiation delivery zone 32. The radiation zone 32comprises an inner balloon wall 36 surrounded by the radiation source10. Preferably, the radiation source 10 is surrounded by an outer sleeve38. In the illustrated embodiment, the radiation source 10 is entrappedbetween the outer sleeve 38 and balloon wall 36, and the outer sleeve 38is adhered to the balloon wall 36 or catheter shaft such as through theuse of thermal bonding or an adhesive. Suitable adhesives includemedical grade UV curable and urethane adhesives known in the art. Any ofa wide variety of alternate techniques known to those of skill in theart can also be utilized for securing an outer sleeve 38 to the balloon,such as fusing, heat shrinking, spot welding, and the like.

[0135] The sleeve 38 may extend only slightly longer in the axialdirection than the axial length of the radiation source 10. The outersleeve 38 can alternatively extend the entire length of the balloon, orlonger, such that it is necked down at the proximal end of the balloonto the catheter shaft and similarly necked down at the distal end of theballoon to the catheter shaft. One suitable outer sleeve 38 comprises0.0003 inch wall thickness PET tube. Other materials could bepolyolefins, nylons, or urethanes, or compounds thereof. Alternatively,the outer sleeve 38 can be omitted, so long as the radiation source 10is adequately secured to the balloon.

[0136] The balloon 26 is mounted on a tubular body 19, which preferablycomprises at least a guidewire lumen 40 and an inflation lumen 42. Inthe illustrated embodiment, the two lumens 40 and 42 are illustrated ina concentric relationship as is known in the art. Alternatively, the twolumens 40 and 42 can be formed in a side-by-side geometry, (FIG. 5) suchas through the use of conventional extrusion techniques.

[0137] Referring to FIG. 5, there is illustrated a perfusion embodimentof the present invention. The radiation delivery catheter with perfusion50 comprises an elongate flexible tubular body 52 having a distalballoon 54 thereon. In this embodiment the tubular body 52 is preferablyconfigured in a side by side orientation, as is well understood in thecatheter art. Thus, the tubular body 52 comprises at least an inflationlumen 56 and a guidewire lumen 58. Additional lumen may be provided,depending upon the desired functionality of the catheter.

[0138] The guidewire lumen 58 extends from the proximal guidewire accessport (not illustrated) to the distal guidewire access port 66 as is wellknown in the art. The proximal guidewire access port may either be onthe side wall of the catheter as has been discussed in a rapid exchangeembodiment, or at the proximal manifold in an over the wire embodiment.A perfusion section 60 of the guidewire lumen 58 extends through theballoon 54, and places a plurality of proximal ports 62 in fluidcommunication with a plurality of distal ports 64. In this manner, theguidewire (not illustrated) can be proximally retracted within theguidewire lumen 58 to a position proximal to the proximal ports 62 oncethe balloon 54 has been positioned at the treatment site. The balloon 54can be inflated by injecting inflation media through the inflation lumen56, and the perfusion section 60 permits blood to perfuse across theballoon by way of proximal ports 62 and distal ports 64.

[0139] As discussed elsewhere herein, the balloon 54 is provided with athin film source 10 which may comprise one or more layers of radioactivethin film source. The thin film source 10 may be adhered to the insidesurface or outside surface of the balloon wall and may be furtherentrapped within an outer tubular layer 70 as illustrated.Alternatively, the thin film source 10 is adhered to the inside surfaceor outside surface of the balloon wall without an outer layer 70.Tubular layer 70 preferably is positioned concentrically about the thinfilm source 10 and heated or bonded to attach to the balloon. The axiallength of the thin film source 10 on, for example, a 3 cm long balloon,may be anywhere within the range of from about 15 mm to about 27 mmmeasured along the axis of the catheter.

[0140] In any of the foregoing embodiments, the isotope layer 16 maycomprise either a homogenous isotope population, or a blend of two ormore isotopes. For example, a blend may be desirable to achieve adesired combination of half life, activity, penetration or othercharacteristics in the finished product. Two or three or four or five ormore different isotopes may be dispersed uniformly throughout theisotope layer 16, or may be concentrated in different zones along theisotope layer, depending upon the desired activity profile in thefinished thin film radiation source.

[0141] In accordance with another aspect of the present invention, thethin film radiation source is applied to a delivery structure such as aballoon in a manner that permits radially asymmetric delivery. This maybe desirable for treating only a selected site within the circumferenceof the arterial wall, such as in the case of an eccentric stenosis.

[0142] In this embodiment radioisotope is provided only along a portionof the circumference of the delivery structure such as a balloon. Theradioisotope zone may comprise anywhere in the range of from about 10%to about 70% of the total circumference of the balloon, and, in oneembodiment, is within the range of from about 30% to about 50% of thetotal circumference of the balloon. This may be accomplished in any avariety of manners, such as masking the thin film prior to applicationof the isotope, applying a blocking layer to block release of radiationfrom portions of the circumference, and the like as will be apparent tothose of skill in the art in view of the disclosure herein. In oneembodiment, a thin film sheet is prepared as has been described herein,except that radioisotope is only adhered to the thin film substrate in aseries of discrete zones which are separated by nonradioactive portionsof substrate. The radioactive zones can be spaced apart along thesubstrate sheet to correspond to the circumference of the deliveryballoon, so that when the radioactive thin film is wrapped around theballoon, the radioactive zones align with each other to provide aradioactive stack on only a predetermined circumferential portion of theballoon.

[0143] Thus, at least a first and a second zone can be provided on thethin film source in accordance with the present invention. In oneembodiment the first zone is radioactive and the second zone is notradioactive. In another embodiment, the first zone has a firstradioactive activity and the second zone has a second, lesserradioactive activity. Alternatively, other characteristics of theradioactive source can be varied between the first zone and the secondzone, depending upon the desired delivery performance.

[0144] In accordance with another aspect of the present invention,balloon catheter may be constructed which allows for delivery ofradiation to differing sizes of lumens. In such a device, the balloonpreferably comprises a compliant plastic material. The substrate for thesource may be either the balloon itself or another thin film of acompliant or elastomeric plastic. As the pressure inside the compliantballoon is increased, the outer diameter of the balloon will increase.Thus, a single balloon catheter may be used to treat different sizelumens by simply varying the pressure and hence the inflation diameterof the balloon.

[0145] The increase in diameter will result in a decrease in density ofisotope atoms per surface area. By adjusting the dwell time, thepredetermined dosage can be delivered. For example, a 20 mm balloonhaving an outer diameter of 2.0 mm and 10¹⁷ atoms of isotope on thesurface will result in a density of 7.96×10¹⁴ atoms/mm². If this balloonwere pressurized to increase to a 2.5 mm diameter, the density woulddecrease to 6.34×10¹⁴ atoms/mm². This is a 20% decrease, resulting in aneed for a 20% increase in dwell time to achieve an equivalent dose.There may also be a slight decrease in balloon length with increaseddiameter of inflation. This change, however, is dependent on the levelof compliance and may be negligible in most cases, but is easilyremedied by careful selection of balloon size.

[0146] In accordance with the method of the present invention, a ballooncatheter such as any described above is percutaneously inserted andtransluminally advanced through a patient's vasculature, to thetreatment site. At the treatment site, the balloon is expanded toposition the radioactive delivery layer against the vessel wall. Theballoon remains expanded for a sufficient radiation delivery time, andis thereafter deflated and withdrawn from the patient. The balloon maybe introduced through an introduction sheath, which can be proximallywithdrawn to expose the balloon once the balloon has been positioned atthe treatment site.

[0147] If delivery times greatly in excess of one or two minutes areclinically desirable, the catheter 18 may be provided with a perfusionconduit such as that illustrated in FIG. 5. Any of a variety ofperfusion structures can be utilized, such as any of those disclosed inU.S. Pat. Nos. 5,344,402 to Crocker entitled Low Profile PerfusionCatheter or 5,421,826 to Crocker et al. entitled Drug Delivery andDilatation Catheter Having a Reinforced Perfusion Lumen, the disclosureof each of which is incorporated in its entirety herein by reference.

[0148] In accordance with another aspect of the method of the presentinvention, the radiation delivery and balloon dilatation catheter of thepresent invention is utilized to simultaneously dilate a stenosis in avessel and deliver a treating dose of radiation. The catheter ispercutaneously introduced and transluminally advanced through thearterial system to reach a stenosis. The balloon is positioned withinthe stenosis, and inflated to expand the stenosis as is known in theart. During the expansion step, the balloon is delivering a treatmentdose of radiation to the vessel wall. The balloon may then be left inposition in the inflated profile optionally with perfusion for asufficient period of time to deliver the desired dose of radiation. Theballoon is thereafter deflated, and the catheter is withdrawn from thetreatment site.

[0149] In accordance with a further aspect of the method of the presentinvention, the radiation delivery catheter of the present invention maybe utilized to simultaneously implant a stent while delivering a dose ofradiation. In accordance with this aspect of the method, a stent ispositioned on the radiation delivery balloon prior to percutaneousinsertion within the patient. The balloon carrying a stent thereon isthereafter percutaneously inserted and transluminally advanced throughthe patient's vasculature to the treatment site. The balloon is expandedat the treatment site to expand the stent, while simultaneouslydelivering a dose of radiation. The balloon is thereafter deflated, andwithdrawn from the patient, leaving the expanded stent in position atthe site.

[0150] In accordance with another aspect of the present invention, thereis provided a method of treating a previously implanted stent or graftwith exposure to a dose of radiation. The method comprises the steps ofidentifying a previously implanted stent or graft within a body lumen. Aradiation delivery catheter of the type described elsewhere herein ispositioned within the stent or graft, and the balloon is inflated toposition the radioactive source against or near the interior wall of thestent or graft The balloon may either be inflated to a sufficientpressure to further dilate the stent or graft, or inflated sufficientlyto position the radiation source against the interior wall of the stentor graft without additional stent or graft expansion or sizing.Following delivery of a dose of radiation, the balloon is deflated andremoved from the patient.

[0151] Any of the foregoing methods may be accomplished either with orwithout the perfusion capability disclosed elsewhere herein. Inaddition, any of the foregoing methods may be accomplished through theuse of an over the wire embodiment of the invention or a rapid exchangeembodiment of the invention as has been disclosed elsewhere herein.

[0152] Thus, in accordance with the present invention, there is provideda catheter having a radiation delivery layer on the balloon, whichpermits a relatively low energy thin film source to be positioneddirectly against, or within about 0.001 inches and preferably no morethan about 0.003 inches from the vascular wall, depending upon thethickness of any outer sleeve 38 or 70 or other coating. In addition,the present configuration expels substantially all blood or other fluidsfrom between the radiation source and the vessel wall, throughout theentire interior circumference of the vessel for the axial length of theballoon. As a consequence, the radiation is not required to penetratemultiple structures as well as blood within the vessel in order to reachthe vessel wall. In addition, radiation delivery is essentially uniformthroughout the entire circumference of the vessel at the delivery site.

[0153] The configuration of the balloon of the present invention is suchthat the radiation delivery layer does not need to be elastic and cansimply be folded with the balloon material into the reduced, insertionprofile. Higher radiation dosages than those specifically describedherein can be readily achieved, such as through the use of longer dosetimes and/or higher activity isotopes and/or higher density of theisotope layer and/or more layers of the thin film source.

[0154] Although the present invention has been described in terms ofcertain preferred embodiments, other embodiments of the invention willbecome apparent to those of skill in the art in view of the disclosureherein. Accordingly, the scope of the present invention is not intendedto be limited by the foregoing, but rather by reference to the attachedclaims.

What is claimed is:
 1. A method of treating a site within a vessel,comprising: identifying a site in a vessel to be treated; providing aradiation delivery catheter including an elongate flexible tubular bodyhaving an expandable balloon with a thin film radiation delivery layerthereon, said thin film comprising a substrate layer and an isotopelayer comprising a metal salt or a metal oxide, and at least oneradioactive isotope; positioning the balloon within the treatment site;inflating the balloon within the treatment site; delivering acircumferentially substantially uniform dose of radiation from thedelivery balloon to the treatment site; deflating the balloon; andremoving the balloon from the treatment site.
 2. A method of treating asite within a vessel as in claim 1, wherein said site comprises apreviously implanted prosthesis, and positioning the balloon comprisespositioning the balloon within the prosthesis.
 3. A method of treating asite within a vessel as in claim 2, wherein the prosthesis comprises astent or graft.
 4. A method of treating a site within a vessel as inclaim 1, wherein said isotope is a gamma or beta emitting isotope.
 5. Amethod of treating a site within a vessel as in claim 1, wherein theradioactive isotope comprises an isotope selected from the groupconsisting of P-32, I-125, Pd-103, W/Re-188, As-73, and Gd-153.
 6. Amethod of treating a site within a vessel as in claim 1, wherein theradiation delivery layer further comprises a tie layer disposed betweenthe support layer and the isotope layer.
 7. A method of treating a sitewithin a vessel as in claim 1, wherein the radiation delivery layerfurther comprises a coating layer upon the isotope layer.
 8. A method oftreating a site within a vessel as in claim 10, wherein said coatinglayer comprises a material selected from the group consisting ofcyanoacrylates, acrylics, acrylates, acrylic acid, urethanes, polybutylvinyl chloride, and polyvinylidine chloride.
 9. A method of treating asite within a vessel as in claim 1, further comprising perfusing bloodfrom a proximal side of the balloon to a distal side of the balloonwhile the balloon is inflated.
 10. A method of treating a site within avessel as in claim 1, wherein the catheter further comprises a proximalguide wire access port on the tubular body, positioned distally of theproximal end of the tubular body.
 11. A method of delivering a dose ofradiation to a lumen, comprising: providing a radiation deliverycatheter including an elongate flexible tubular body having a radiationdelivery layer carried by an expandable support on the tubular body,said radiation delivery layer comprising a substrate layer and anisotope layer comprising a metal salt or a metal oxide, and at least oneradioactive isotope; positioning the expandable support within thelumen; radially expanding the support within the lumen; delivering acircumferentially substantially uniform dose of radiation to the lumenin the region of the radiation delivery layer; radially contracting thesupport; and removing the support from the lumen.
 12. A method as inclaim 11, wherein radially expanding the support comprises inflating aninflatable balloon.
 13. A method as in claim 11, further comprisingperfusing blood from a proximal side of the expandable support to adistal side of the expandable support while the support is expanded. 14.A method of treating a site within a vessel as in claim 11, wherein saidisotope is a gamma or beta emitting isotope.
 15. A method as in claim11, wherein the radioactive isotope comprises an isotope selected fromthe group consisting of P-32, I-125, Pd-103, W/Re-188, As-73, andGd-153.
 16. A method as in claim 11, wherein the radiation deliverylayer further comprises a tie layer disposed between the support layerand the isotope layer.
 17. A method as in claim 11, wherein theradiation delivery layer further comprises a coating layer upon theisotope layer.
 18. A method as in claim 17, wherein said coating layercomprises a material selected from the group consisting ofcyanoacrylates, acrylics, acrylates, acrylic acid, urethanes, polybutylvinyl chloride, and polyvinylidine chloride.
 19. A method as in claim11, wherein the catheter further comprises a proximal guide wire accessport on the tubular body, positioned distally of the proximal end of thetubular body.
 20. A method as in claim 11, wherein the substrate layeris integral with the support.
 21. A method as in claim 11, wherein thesubstrate layer is layered upon the support.
 22. A method as in claim11, wherein positioning the support comprises positioning the isotopelayer within a stent.
 23. A method as in claim 11, wherein the lumen isselected from the group consisting of large and small arteries, largeand small veins, hollow organs, surgically created pathways, esophagus,trachea, urethra, ureters, fallopian tubes, intestines and colon.
 24. Amethod of simultaneously performing balloon dilatation of a stenosis ina body lumen and delivering radiation to the body lumen, comprising:identifying a stenosis in a body lumen; providing a treatment catheterhaving an elongate flexible tubular body having an expandable balloonwith a thin film radiation delivery layer thereon, said thin filmcomprising a substrate layer and an isotope layer comprising a metalsalt or a metal oxide, and at least one radioactive isotope;percutaneously inserting and transluminally advancing the balloonthrough the vessel; positioning the balloon within the stenosis;inflating the balloon to radially expand the vessel in the area of thestenosis; and simultaneously delivering radiation from the thin film tothe vessel wall.
 25. A method of simultaneously delivering a stent andradiation to a treatment site in body lumen, comprising: identifying atreatment site in a body lumen; providing a treatment catheter having anelongate flexible tubular body having a radially expandable support witha thin film radiation delivery layer thereon and an expandable stentcarried by the expandable support, said thin film comprising a substratelayer and an isotope layer comprising a metal salt or a metal oxide, andat least one radioactive isotope; positioning the support at thetreatment site in the lumen; radially expanding the support to expandand deliver the stent; and simultaneously delivering radiation from thethin film to the lumen wall.